Inherited disorders

Miscellaneous Metabolic disorders—ketoacidosis, acute renal failure, eclampsia, acute poisoning
Drugs—lithium
Other—metastatic carcinoma, acute hemorrhage or hemolysis
Abnormal Neutrophil Function
Inherited and acquired abnormalities of phagocyte function are listed in Table 61-3. The resulting diseases are best considered in terms of the functional defects of adherence, chemotaxis, and microbicidal activity. The distinguishing
features of the important inherited disorders of phagocyte function are shown in Table 61-4.

Factor XI Deficiency: Treatment The treatment of FXI deficiency is based on the infusion of FFP at doses of 15–20 mL/kg to maintain trough levels ranging from 10 to 20%. Because FXI has a half-life of 40–70 h, the replacement therapy can be given on alternate days. The use of antifibrinolytic drugs is beneficial to control bleeds, with the exception of hematuria or bleeds in the bladder. The development of a FXI inhibitor was observed in 10% of severely FXI-deficient patients who received replacement therapy.

Approach to the Patient: Thrombocytopenia The history and physical examination, results of the CBC, and review of the peripheral blood smear are all critical components in the initial evaluation of the thrombocytopenic patients (Fig. 109-2). The overall health of the patient and whether he/she is receiving drug treatment will influence the differential diagnosis. A healthy young adult with thrombocytopenia will have a much more limited differential diagnosis than an ill hospitalized patient who is receiving multiple medications.

Diseases of the neuromuscular junction (NMJ) include a large spectrum of
acquired and inherited disorders mainly characterized by fluctuating muscle
weakness and fatigability of ocular, bulbar or limb muscles. Remarkable
progress has been made in our understanding of the pathogenesis of these
disorders in recent years.

A quick win in personalised medicine could be in the area of rare inherited disorders, of which most are
life-threatening or seriously debilitating. Currently, 6000-8000 rare inherited disorders are known and
the genetic basis of around halve has been resolved. About a thousand are currently treatable and taken
together all rare inherited disorders place a major burden on Europe’s health care systems.

Harrison's Internal Medicine Chapter 99. Disorders of Hemoglobin
Disorders of Hemoglobin: Introduction
Hemoglobin is critical for normal oxygen delivery to tissues; it is also present in erythrocytes in such high concentrations that it can alter red cell shape, deformability, and viscosity. Hemoglobinopathies are disorders affecting the structure, function, or production of hemoglobin. These conditions are usually inherited and range in severity from asymptomatic laboratory abnormalities to death in utero.

Dr. Sharon Rounds, the editor for this series who invited us to write a book on rare
lung diseases, developed the idea after attending the 2004 Lymphangioleiomyomatosis
(LAM) Foundation annual research meeting. She was a keynote speaker at that event
(during her tenure as the president of the American Thoracic Society) and was witness
to the power of patient advocacy and the mission-based scientific effort that had
brought this rare disease of women from obscurity to clinical trials with targeted molecular
therapies in under a decade.

Chronic Granulomatous Disease Chronic granulomatous disease (CGD) is a group of disorders of granulocyte and monocyte oxidative metabolism. Although CGD is rare, with an incidence of 1 in 200,000 individuals, it is an important model of defective neutrophil oxidative metabolism. Most often CGD is inherited as an X-linked recessive trait; 30% of patients inherit the disease in an autosomal recessive pattern. Mutations in the genes for the four proteins that assemble at the plasma membrane account for all patients with CGD.

Severity is highly variable. Known modulating factors are those that ameliorate the burden of unpaired α-globin inclusions. Alleles associated with milder synthetic defects and co-inheritance of α-thalassemia trait reduce clinical severity by reducing accumulation of excess α globin. HbF persists to various degrees in β-thalassemias. γ-Globin gene chains can substitute for βchains, generating more hemoglobin and reducing the burden of α-globin inclusions. The terms β-thalassemia major and β-thalassemia intermedia are used to reflect the clinical heterogeneity.

Hemoglobin E HbE (i.e., α2β226Glu - Lys) is extremely common in Cambodia, Thailand, and Vietnam. The gene has become far more prevalent in the United States as a result of immigration of Asian persons, especially in California, where HbE is the most common variant detected. HbE is mildly unstable but not enough to affect RBC life span significantly. The high frequency of the HbE gene may be a result of the thalassemia phenotype associated with its inheritance. Heterozygotes resemble individuals with mild β-thalassemia trait.

Thrombocytopenia Thrombocytopenia results from one or more of three processes: (1) decreased bone marrow production; (2) sequestration, usually in an enlarged spleen; and/or (3) increased platelet destruction.
Disorders of production may be either inherited or acquired. In evaluating a patient with thrombocytopenia, a key step is to review the peripheral blood smear and to first rule out "pseudothrombocytopenia," particularly in a patient without an apparent cause for the thrombocytopenia.
Pseudothrombocytopenia (Fig.

Thrombotic Thrombocytopenic Purpura TTP and HUS were previously considered overlap syndromes. However, in the past few years the pathophysiology of inherited and idiopathic TTP has become better understood and clearly differs from HUS. TTP was first described in 1924 by Eli Moschcowitz and characterized by a pentad of findings that include microangiopathic hemolytic anemia, thrombocytopenia, renal failure, neurologic findings, and fever. The full-blown syndrome is less commonly seen now, probably due to earlier diagnosis.

von Willebrand Disease vWD is the most common inherited bleeding disorder. Estimates from laboratory data suggest a prevalence of approximately 1%, but data based on symptomatic individuals suggest that it is closer to 0.1% of the population. vWF serves two roles: (1) as the major adhesion molecule that tethers the platelet to the exposed subendothelium; and (2) as the binding protein for FVIII, resulting in significant prolongation of the FVIII half-life in circulation.

There are a wide range of problems that are considered psychological
disorders, including mental and emotional disorders, problems
related to alcohol and drug abuse, and some diseases that cause both
emotional and physical symptoms. Psychological disorders often begin in
early childhood, but during adolescence we see a sharp increase in the
number of people affected by these disorders. It has been estimated that
about 20 percent of the U.S. population will have some form of mental
disorder sometime during their lifetime. Some psychological disorders
appear following severe stress or trauma.

This chapter include objectives: Evaluate the effects of continuous variation, pleiotropic genes, lack of complete dominance, environmental modifications of genes, and epistasis on disease; understand the importance of crossing over in terms of gene assortment and construction of genetic maps; describe the many genetic disorders discussed in the text, their symptoms, relative frequency in specialized populations, and their genetic basis;...

Patients aﬀected by bleeding disorders present a
wide spectrum of clinical symptoms that vary from a mild or
moderate bleeding tendency to signiﬁcant episodes. Women
with inherited bleeding disorders are particularly disadvantaged
since, in addition to suﬀering from general bleeding symptoms,
they are also at risk of bleeding complications from regular
haemostatic challenges during menstruation, pregnancy and
childbirth.

Recall of family history is often inaccurate. This is especially so when the history is remote and families become more dispersed geographically. It can be helpful to ask patients to fill out family history forms before or after their visits, as this provides them with an opportunity to contact relatives. Attempts should be made to confirm the illnesses reported in the family history before making important and, in certain circumstances, irreversible management decisions.